The purpose of this study was to determine the role which chronic exposure to ethanol and its metabolic product acetate play in altering the function of the immune system in alcoholics and subjects with alcoholic hepatitis and alcoholic cirrhosis. Earlier we had shown that elevation of plasma tumor necrosis factor ` (TNF `) predicted death in patients with severe alcoholic hepatitis. Elevation of no other acute Phase cytokine was found to do so, nor was there a correlation with standard liver function tests, nor with abstinence after discharge from 30 days in hospital. In order to further examine alterations in immune function in alcoholics we determined this year, that plasma levels of interferon gamma(IFNgamma) were elevated in alcoholic subjects without clinically obvious liver disease during withdrawal from alcohol. Correlated with this elevation of IFNgamma, there was the expected increase in the expression of MHC class I antigens circulating mononuclear cells, but a paradoxical decrease in expression of MHC class II protein on the cell surface of circulating leukocytes. Finally, it was determined that end stage renal disease patients, exposed to 1.5 mM acetate but without exposure to ethanol as a precursor showed acute elevation within 4 hours of circulating transforming growth factor ~ (TGF~) during hemodialysis. TGF~ is associated with the production of fibrosis and collagen formation, a prominent feature of alcoholic cirrhosis, while TNFalpha is associated with cell death, also a prominent feature of alcoholic cirrhosis and alcoholic hepatitis. This finding of widespread abnormalities in alcoholics begin to present a coherent pattern of alteration in immune function by ethanol and its metabolite acetate which may have clinical significance not only for our understanding of pathogenesis, but also for improved treatment of the severe and often fatal medical consequences of alcoholism. These findings also have implications for HIV-1 infection and progression of disease in a group of poly drug abusers, who also abuse alcohol, and constitute a high risk group for HIV-1 infection.